PDLLA stent coating

ABSTRACT

An amorphous PDLLA stent coating for drug delivery is disclosed.

CROSS-REFERENCE

This application is a Continuation of application Ser. No. 14/259,458filed on Apr. 23, 2014, which is a Continuation of application Ser. No.11/022,228 filed Dec. 23, 2004, now U.S. Pat. No. 8,741,378, issued Jun.3, 2014, which is a Continuation-In-Part of application Ser. No.09/894,293 filed Jun. 27, 2001, which is abandoned, the entire contentsof which are hereby incorporated by reference for all purposes.

BACKGROUND

Blood vessel occlusions are commonly treated by mechanically enhancingblood flow in the affected vessels, such as by employing a stent. Stentsact as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically stents arecapable of being compressed, so that they can be inserted through smalllumens via catheters, and then expanded to a larger diameter once theyare at the desired location. Examples in the patent literaturedisclosing stents include U.S. Pat. No. 4,733,665 issued to Palmaz, U.S.Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062issued to Wiktor.

FIG. 1 illustrates a conventional stent 10 formed from a plurality ofstruts 12. The plurality of struts 12 are radially expandable andinterconnected by connecting elements 14 that are disposed betweenadjacent struts 12, leaving lateral openings or gaps 16 between adjacentstruts 12. Struts 12 and connecting elements 14 define a tubular stentbody having an outer, tissue-contacting surface and an inner surface.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy can beachieved by medicating the stents. Medicated stents provide for thelocal administration of a therapeutic substance at the diseased site.Local delivery of a therapeutic substance is a preferred method oftreatment because the substance is concentrated at a specific site andthus smaller total levels of medication can be administered incomparison to systemic dosages that often produce adverse or even toxicside effects for the patient.

One method of medicating a stent involves the use of a polymeric carriercoated onto the surface of the stent. A composition including a solvent,a polymer dissolved in the solvent, and a therapeutic substancedispersed in the blend is applied to the stent by immersing the stent inthe composition or by spraying the composition onto the stent. Thesolvent is allowed to evaporate, leaving on the stent strut surfaces acoating of the polymer and the therapeutic substance impregnated in thepolymer.

A shortcoming of the above-described method of medicating a stent is thepotential for coating defects due to the large amount of liquidcomposition applied to the relatively small surface area of the stent.The liquid composition can flow, wick, and collect as the amount ofcomposition on the stent increases during the coating process. As thesolvent evaporates, the excess composition hardens, leaving the excesscoating as clumps or pools on the struts or webbing between the struts.

Another shortcoming of the above-described method of medicating a stentis the potential for loss of the therapeutic substance from the coatingor production of a coating that does not provide for a suitableresidence time of the substance at the implanted region. Initialportions of a liquid composition containing a therapeutic substancesprayed onto a stent adhere to the stent surface. However, as the liquidcomposition continues to be applied to the stent, layers of thecomposition are formed on top of one another. When exposed to thesolvent in the upper layers, the therapeutic substance in the lowerlayers can be re-dissolved into the upper layers of the composition orextracted out from the coating. Having the therapeutic substancemaintained in merely the upper regions of the coating provides for ashort residence time of the substance at the implanted region, as thetherapeutic substance will be quickly released. Prolonged residencetimes in situ may be desirable for a more effective treatment of apatient.

The present invention addresses such problems by providing methods ofcoating implantable devices.

SUMMARY

A stent is disclosed comprising a coating, the coating consisting of apoly(D,L-lactic acid) (PDLLA) and a macrocyclic drug, wherein the PDLLAhas a degree of crystallinity of less than 20 percent, the measurementbeing by weight of the amount of polymer that is in the form ofcrystallites as measured by differential scanning calorimetry, whereinthe coating has a thickness of 0.05 microns to 10 microns, and whereinthe stent on which the coating is disposed is made from a bioabsorbablypolymer.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a conventional stent.

DETAILED DESCRIPTION

This document incorporates by this reference the entire disclosure ofU.S. patent application Ser. No. 09/894,293, which was filed on Jun. 27,2001.

For ease of discussion, the methods detailed herein will be describedwith reference to coating a stent. However, the device or prosthesiscoated in accordance with embodiments of the present invention may beany suitable medical substrate that can be implanted in a human orveterinary patient. Examples of such implantable devices includeself-expandable stents, balloon-expandable stents, stent-grafts, grafts(e.g., aortic grafts)), artificial heart valves, cerebrospinal fluidshunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE andENDOTAK, available from Guidant Corporation). The underlying structureof the device can be of virtually any design. The device can be made ofa metallic material or an alloy such as, but not limited to, cobaltchromium alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention. In some embodiments, theimplantable device is chosen to specifically exclude any one or anycombination of self-expandable stents, balloon-expandable stents,stent-grafts, grafts (e.g., aortic grafts), artificial heart valves,cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads(e.g., FINELINE and ENDOTAK, available from Guidant Corporation). Insome embodiments, the implantable device is not a catheter. In someembodiments in which the implantable device can be chosen to be acatheter, the implantable device is chosen not to be a catheter liner.

The methods of some embodiments of the current invention compriseadjusting the temperature of an implantable portion of a medical deviceto a target temperature, which is always non-ambient, and then coatingthe implantable portion of the medical device with a coating substance.In some embodiments, adjusting occurs such that the increase or decreasein temperature only occurs before applying the coating substance begins.In other embodiments, adjusting occurs such that heating or coolingstarts before and continues during the applying step or the adjustingand applying steps occur substantially together.

Different invention embodiments employ different “adjusting” profiles.For instance, in some profiles, the implantable device is adjusted tothe target temperature before applying a coating substance and thenapplying occurs (with or without some amount of temperature decreasebefore crimping); alternatively, the implantable device is adjusted tothe target temperature before applying a coating substance andmaintained at or near the target temperature during applying;alternatively, applying is started, the implantable medical device isadjusted to the target temperature, and applying is completed. In someembodiments, applying begins before the implantable device has reachedthe target temperature and continues until or after the targettemperature has been reached.

For purposes of this disclosure, ambient temperature is the temperatureof the implantable device when it has not been purposely heated orcooled. In alternative embodiments, ambient temperature is roomtemperature, 25-30° C., 20-30° C., 20-25° C., 23-27° C. or 10-30° C.Similarly, for purposes of this disclosure, a target temperature is atemperature numerically different from ambient temperature. In someembodiments, the difference between the target temperature and ambientis brought about by purposely heating or cooling the implantable device.

A target temperature is chosen based on the characteristics of thecomponents of the coating substance. For instance, if the solvent of thecoating substance is non-volatile or has a low volatility, the targettemperature can be chosen to be above ambient temperature to improve theevaporation rate. Conversely, if the coating substance solvent isvolatile, the target temperature can be chosen to be below ambienttemperature to lower the evaporation rate. The identity of the solventis not the only characteristic upon which a target temperature can bebased. For instance, if the coating substance comprises a therapeuticsubstance, the target temperature can be chosen to minimize thermaldegradation of the therapeutic substance. Alternatively, if a polymer isused in the coating substance, the target temperature can be chosenabove Tg of the polymer to improve its flow characteristics duringdeposition. In other embodiments, if the solvent of the coatingsubstance has a high boiling point, the target temperature can be chosento be above ambient temperature to improve the evaporation rate.Conversely, if the coating substance solvent has a low boiling point,the target temperature can be chosen to be below ambient temperature tolower the evaporation rate. Similarly, if the solvent is likely tofreeze at ambient temperature during the applying step, the targettemperature can be chosen to maintain it in a molten state to facilitateits removal. Those of ordinary skill in the art will be able to identifyother characteristics of components of the coating substance that can beimproved by applying the substances to an implantable device that is ata non-ambient target temperature.

In some embodiments, the target temperature is chosen to be aboveambient temperature if the solvent is non-volatile or has lowvolatility. In some embodiments, non-volatile and having low volatilitytake their standard meanings as recognized by those of ordinary skill inthe art. In these or other embodiments, nonvolatile and having lowvolatility means that the solvent has a volatility such that it does notsubstantially evaporate in a scientifically or commercially reasonabletime as that time would be understood by one of ordinary skill in theart.

In some embodiments, non-volatile or having a low volatility means thatwhen a solution composed of at least the solvent is applied to animplantable device the solvent does not substantially evaporate within30 sec, 60 sec, 2 min, 5 min, 10 min, 15 min, 30 min, or 60 min atambient temperature and pressure. In some embodiments, the targettemperature is chosen to be below ambient temperature if the solvent isvolatile. In some embodiments, volatile takes its standard meanings asrecognized by those of ordinary skill in the art. In these or otherembodiments, volatile means the solvent substantially evaporates fastenough to compromise the coating in a scientifically or commerciallyunreasonable manner as that would be understood by one of ordinary skillin the art. In some embodiments, volatile means that when a solutioncomposed of at least the solvent is applied to an implantable device thesolvent substantially evaporates within <30 sec, <20 sec, <15 sec, <10sec, <8 sec, <5 sec, <4 sec, <3 sec, <2 see, or <1 sec at ambienttemperature and pressure. In some embodiments, the target temperature ischosen to be below the decomposition region for a therapeutic substance.

In some embodiments that use coating substances to form primer layers,the target temperature can be chosen higher than ambient. In someembodiments that use coating substances to form topcoat layers, thetarget temperature can be chosen close to ambient or lower than ambienttemperature.

In some embodiments, adjusting the temperature of the implantable devicecomprises adjusting the temperature to a target temperature and thenletting the temperature fluctuate thereafter.

In some embodiments, adjusting the temperature of the implantablemedical device to a target temperature means adjusting the temperatureto within ±1° C., ±2° C., ±3° C., ±4° C., ±5° C., ±6° C., ±8° C., ±9°C., ±10° C., ±12° C., ±15° C., or ±20° C. of the target temperaturebefore, during, or after the applying step begins.

“Adjusting” the temperature of the medical device comprises placing theobject that is to have its temperature adjusted into thermal contactwith a heat source. For purposes of this disclosure, thermal contactwith a heat source means heat source arrangement vis-à-vis the object sothat energy would flow or be carried from the heat source to the object.Thermal contact is a generic term at least encompassing an arrangementof the object such that radiation, conduction, or convection from theheat source would transfer energy. In some embodiments, thermal contactis defined to exclude any of radiation, conduction, convection, or anycombination of these. Furthermore no invention embodiments use aconvection oven or an ultrasound energy source.

In some embodiments, “maintained near the target temperature” means thatthe temperature of the implantable device, when it contacts the coatingsubstance, is the same as the target temperature or within ±1° C., ±2°C., ±3° C., ±4° C., ±5° C., ±6° C., ±7° C., ±8° C., ±9° C., ±10° C.,±12° C., ±15° C., or ±20° C. of the target temperature.

In some embodiments, “maintained at the target temperature during theapplying step” means keeping the temperature of the implantable devicethe same as the target temperature or within ±1° C., ±2° C., ±3° C., ±4°C., ±5° C., ±6° C., ±7° C., ±8° C., ±9° C., ±10° C., ±12° C., ±15° C.,or ±20° C. of the target temperature.

The applying step forms a coating on an implantable medical device suchas a stent; it is accomplished in some embodiments by spraying acomposition onto the stent. A spray apparatus, such as EFD 780S spraydevice with VALVEMATE 7040 control system (manufactured by EFD Inc.,East Providence, R.I.), can be used to apply the composition to thestent. EFD 780S spray device is an air-assisted external mixingatomizer. The composition is atomized into small droplets by air anduniformly applied to the stent surfaces. The atomization pressure can bemaintained at a range of about 5 psi to about 20 psi. The droplet sizedepends on factors such as viscosity of the solution, surface tension ofthe solvent, and atomization pressure. Other types of spray applicators,including air-assisted internal mixing atomizers and ultrasonicapplicators, can also be used for the application of the composition.

During the application of the composition, the stent can be rotatedabout the stent's central longitudinal axis. Rotation of the stent canbe from about 0.1 rpm to about 300 rpm, more narrowly from about 1 rpmto about 10 rpm. By way of example, the stent can rotate at about 3 rpm.The stent can also be moved in a linear direction along the same axis.The stent can be moved at about 1 mm/second to about 12 min/second, forexample about 6 mm/second, or for a minimum of at least two passes(i.e., back and forth past the spray nozzle).

The flow rate of the composition from the spray nozzle can be from about0.01 mg/second to about 1.0 mg/second, more narrowly about 0.1mg/second. Only a small percentage of the composition that is deliveredfrom the spray nozzle is ultimately deposited on the stent. By way ofexample, when a composition is sprayed to deliver about 1 mg of solids,only about 100 micrograms or about 10% of the solids sprayed will likelybe deposited on the stent. Multiple repetitions for applying thecomposition can be performed, wherein each repetition can be, forexample, about 0.5 second to about 5 seconds in duration. In these orother embodiments, the steps can be repeated 2-100, 2-50, 30-100, 20-50,50-100, or greater than 100 times. The amount of coating applied by eachrepetition can be about 1 microgram/cm² (of stent surface) to about 50micrograms/cm², for example less than about 20 micrograms/cm² per1-second spray.

Each repetition can be followed by removal of a significant amount ofthe solvent(s). The removal of the solvent(s) can be performed followinga waiting period of about 0.1 second to about 5 seconds after theapplication of the coating composition so as to allow the liquidsufficient time to flow and spread over the stent surface before thesolvent(s) is removed to form a coating. The waiting period isparticularly suitable if the coating composition contains a volatilesolvent, such as solvents having boiling points >130° C. at ambientpressure, since such solvents are typically removed quickly.

The applying step excludes immersing the temperature-adjustedimplantable device into the coating substance.

Removal of the solvent(s) can be induced by the application of a warmgas. The application of a warm gas between each repetition preventscoating defects and minimizes interaction between the active agent andthe solvent. Any suitable gas can be employed, examples of which includeair or nitrogen. The temperature of the warm gas can be from about 25°C. to about 200° C., more narrowly from about 40° C. to about 90° C. Theflow speed of the gas can be from about 0.5 feet³/second (0.01meters³/second) to about 50 feet³/second (1.42 meters³/second), morenarrowly about 2.5 feet³/second (0.07 meters³/second) to about 15feet³/second (0.43 meters³/second). The gas can be applied for about 1second to about 100 seconds, more narrowly for about 2 seconds to about20 seconds. By way of example, warm gas applications can be performed ata temperature of about 60° C., at a flow speed of about 10 feet³/second,and for about 10 seconds.

In one embodiment, the stent can be warmed to a temperature of fromabout 35° C. to about 80° C. prior to the application of the coatingcomposition so as to facilitate faster removal of the solvent(s). Theparticular temperature selected depends, at least in part, on theparticular active agent employed in the coating composition. By way ofexample, pre-heating of the stent prior to applying a compositioncontaining actinomycin D should be performed at a temperature notgreater than about 55° C. Pre-heating is particularly suitable forembodiments in which the solvent(s) employed in the coating compositionhas a high boiling point, i.e., volatile solvents having boiling pointsof, for example, >130° C. at ambient pressure (e.g., dimethylsulfoxide(DMSO), dimethylformamide (DMF), and dimethylacetamide (DMAC)).

Any suitable number of repetitions of applying the composition followedby removing the solvent(s) can be performed to form a coating of adesired thickness or weight. Excessive application of the polymer can,however, cause coating defects. In embodiments in which the coatingcomposition contains a volatile solvent, a waiting period of from about0.1 second to about 20 seconds can be employed between solvent removalof one repetition and composition application of the subsequentrepetition so as to ensure that the wetting rate of the coatingcomposition is slower than the evaporation rate of the solvent withinthe composition, thereby promoting coating uniformity.

Operations such as wiping, centrifugation, or other web clearing actscan also be performed to achieve a more uniform coating. Briefly, wipingrefers to the physical removal of excess coating from the surface of thestent; and centrifugation refers to rapid rotation of the stent about anaxis of rotation. The excess coating can also be vacuumed off of thesurface of the stent.

In accordance with one embodiment, the stent can be at least partiallypre-expanded prior to the application of the composition. For example,the stent can be radially expanded about 20% to about 60%, more narrowlyabout 27% to about 55%—the measurement being taken from the stent'sinner diameter at an expanded position as compared to the inner diameterat the unexpanded position. The expansion of the stent, for increasingthe interspace between the stent struts during the application of thecomposition, can further prevent “cob web” formation between the stentstruts.

A final heat treatment can be conducted to remove essentially all of thesolvent(s) from the composition on the stent. The heat treatment can beconducted at about 30° C. to about 200° C. for about 15 minutes to about16 hours, more narrowly at about 50° C. to about 100° C. for about 1hour to about 4 hours. By way of example, the heat treatment can beconducted at about 75° C. for 1 hour. The temperature of exposure shouldnot adversely affect the characteristics of the active agent or of thecoating. The heating can be conducted in an anhydrous atmosphere and atambient pressure. The heating can, alternatively, be conducted under avacuum condition. It is understood that essentially all of thesolvent(s) will be removed from the composition but traces or residuescan remain blended in the coating.

By way of example, and not limitation, the coating, referred to hereinas the primary or reservoir coating, can have a thickness of about 0.05microns to about 10 microns. The particular thickness of the coating isbased on the type of procedure for which the stem is employed and theamount, if any, of active agent that is desired to be delivered.Applying a plurality of reservoir coating layers, containing the same ordifferent active agents, onto the stent can further increase the amountof the active ingredient to be carried by the stent, without causingcoating defects.

In accordance with one embodiment, the coating substance can include asolvent and a polymer dissolved in the solvent. The coating substancecan also include active agents, radiopaque elements, or radioactiveisotopes. Representative examples of polymers that can be used to coat astent include ethylene vinyl alcohol copolymer (commonly known by thegeneric name EVOH or by the trade name EVAL), poly(hydroxyvalerate);poly(L-lactic acid); polycaprolactone; poly(lactide-coglycolide);poly(hydroxybutyrate); poly(hydroxybutyrate-co-valerate); polydioxanone;polyorthoester; polyanhydride; poly(glycolic acid); poly(D,L-lacticacid); poly(glycolic acid-co-trimethylene carbonate); polyphosphoester;polyphosphoester urethane; poly(amino acids); cyanoacrylates;poly(trimethylene carbonate); poly(iminocarbonate); copoly(ether-esters)(e.g. PEO/PLA); polyalkylene oxalates; polyphosphazenes; biomolecules,such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid; polyurethanes; silicones; polyesters; polyolefins; polyisobutyleneand ethylene-alphaolefin copolymers; acrylic polymers and copolymers;vinyl halide polymers and copolymers, such as polyvinyl chloride;polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidenehalides, such as polyvinylidene fluoride and polyvinylidene chloride;polyacrylonitrile; polyvinyl ketones; polyvinyl aromatics, such aspolystyrene; polyvinyl esters, such as polyvinyl acetate; copolymers ofvinyl monomers with each other and olefins, such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 andpolycaprolactam; alkyd resins; polycarbonates; polyoxyrnethylenes;polyimides; polyethers; epoxy resins; polyurethanes; rayon;rayon-triacetate; cellulose; cellulose acetate; cellulose butyrate;cellulose acetate butyrate; cellophane; cellulose nitrate; cellulosepropionate; cellulose ethers; and carboxymethyl cellulose.

In some embodiments, the polymer or the processing conditions of themethod are selected such that the polymer is non-crystalline. Acrystalline polymer is one in which upon analysis a detectable patternmay be observed when using conventional x-ray scattering techniques.Such conventional techniques are disclosed, for example, in “TheStructure of Crystalline Polymers”, Tadokoro, H. (Wiley Interscience,1979). The degree of crystallinity of a polymer is the measurement byweight of the amount of polymer that is in the form of crystallites, asmeasured by differential scanning calorimetry. For purposes of thisdisclosure, a polymer that is noncrystalline has a degree ofcrystallinity of less than about 20 percent.

“Solvent” is defined as a liquid substance or composition that iscompatible with the polymer and is capable of dissolving the polymer atthe concentration desired in the composition. Examples of solventsinclude, but are not limited to, dimethylsulfoxide (DMSO), chloroform,acetone, water (buffered saline), xylene, methanol, ethanol, 1-propanol,tetrahydrofuran, 1-butanone, dimethylformamide, dimethylacetamide,cyclohexanone, ethyl acetate, methylethylketone, propylene glycolmonomethylether, isopropanol, isopropanol admixed with water, N-methylpyrrolidinone, toluene, and combinations thereof.

The therapeutic agent can inhibit vascular, smooth muscle cell activity.More specifically, the therapeutic agent can aim at inhibiting abnormalor inappropriate migration or proliferation of smooth muscle cells toprevent, inhibit, reduce, or treat restenosis. The therapeutic agent canalso include any substance capable of exerting a therapeutic orprophylactic effect in the practice of the present invention. Usefultherapeutic agents can include therapeutic agents selected formantibiotics; anticoagulants; antifibrins; antiinflammatories;antimitotics; antineoplastics; antioxidants; antiplatelets;antiproliferatives; antithrombins; and their combinations. Other usefultherapeutic agents include actinomycin D or derivatives and analogsthereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue,Milwaukee, Wis. 53233; or COSMEGEN available from Merck); dactinomycin;actinomycin IV; actinomycin I₁; actinomycin X₁; actinomycin C₁apaclitaxel; docetaxel; aspirin; sodium heparin; low molecular weightheparin; hirudin; argatroban; forskolin; vapiprost; prostacyclin;prostacyclin analogs; dextran; D-phe-pro-arg-chloromethylketone(synthetic antithrombin); dipyridarnole; glycoprotein IIb/IIIa plateletmembrane receptor antagonist; recombinant hirudin; thrombin inhibitor(available from Biogen); 7E-3B® (an antiplatelet drug from Centocor);methotrexate; azathioprine; vincristine; vinblastine; fluorouracil;adriamycin; mutamycin; angiopeptin (a somatostatin analog from Ibsen);angiotensin converting enzyme inhibitors; CAPTOPRIL (available fromSquibb); CILAZAPRIL (available from Hoffman-LaRoche); LISINOPRIL(available from Merck & Co., Whitehouse Station, N.J.); calcium channelblockers; Nifedipine; colchicinefibroblast growth factor (FGF)antagonists; histamine antagonist; LOVASTATIN (an inhibitor of HMG-CoAreductase, a cholesterol lowering drug from Merck &Co.); monoclonalantibodies (such as PDGF receptors); nitroprusside; phosphodiesteraseinhibitors; prostaglandin inhibitor (available from Glazo); Seramin (aPDGF antagonist); serotonin blockers; thioprotease inhibitors;triazolopyrimidine (a PDGF antagonist); nitric oxide; alpha-interferon;genetically engineered epithelial cells; dexamethasone; estradiol;clobetasol propionate; cisplatin; insulin sensitizers; receptor tyrosinekinase inhibitors; carboplatin; Rapamycin;40-O-(2-hydroxyl)ethyl-rapamycin, or a functional analog or structuralderivative thereof; 40-O-(3-hydroxyl)propyl-rapamycin;40-O-2-(2-hydroxyl)ethoxyethyl-rapamycin and their combinations.

Individual embodiments exist in which the therapeutic agent is selectedto specifically exclude any one of or any combination of the therapeuticagents or therapeutic agent families described above.

Some invention embodiments comprise a therapeutic agent or therapeuticagent combination, and some require a therapeutic agent or combinationof therapeutic agents. Of the therapeutic agents specifically listedabove, some invention embodiments exclude a single or any combination ofthese therapeutic agents.

Examples of radiopaque elements include, but are not limited to, gold,tantalum, and platinum. An example of a radioactive isotope is P³².Sufficient amounts of such substances may be dispersed in thecomposition such that the substances are not present in the compositionas agglomerates or flocs.

The methods for coating an implantable device, such as a stent,according to embodiments of the present invention, can be used to createa multi-layer structure that can include any one or any combination ofthe following four layers:

(a) a primer layer;

(b) a drug-polymer layer (also referred to as “reservoir” or “reservoirlayer”) or a polymer-free drug layer; and

(c) a topcoat layer, which is likewise drug containing or drug free.

(d) a finishing layer, for biocompatibility possessing biobeneficialproperties.

In some embodiment, an optional primer layer can be formed prior to theprimary or reservoir coating to increase the retention of the primary orreservoir coating on the surface of the stent, particularly metallicsurfaces such as stainless steel. The primer layer can act as anintermediary adhesive tie layer between the surface of the device and areservoir coating carrying an active agent, allowing for the quantity ofthe active agent to be increased in the reservoir coating.

To form an optional primer layer on the surface of the stent, anembodiment of the above-described composition that is free from activeagents is applied to the surface of the stent. Ethylene vinyl alcoholcopolymer, for example, adheres very well to metallic surfaces,particularly stainless steel. Accordingly, the copolymer provides for astrong adhesive tie between the reservoir coating and the surface of thestent. With the use of thermoplastic polymers such as, but not limitedto, ethylene vinyl alcohol copolymer, polycaprolactone,poly(lactide-co-glycolide), and poly(hydroxybutyrate), the depositedprimer composition should be exposed to a heat treatment at atemperature range greater than about the glass transition temperature(T_(g)) and less than about the melting temperature (T_(m)) of theselected polymer. Unexpected results have been discovered with treatmentof the composition under this temperature range, specifically strongadhesion or bonding of the coating to the metallic surface of the stent.The prosthesis should be exposed to the heat treatment for any suitableduration of time that will allow for the formation of the primer layeron the surface of the stent and for the evaporation of the solventemployed. By way of example and not limitation, the optional primerlayer can have a thickness of about 0.01 microns to about 2 microns. Theapplication of the primary or reservoir coating should be performedsubsequent to the drying of the optional primer layer.

In another embodiment, an optional diffusion barrier can be formed overa reservoir coating containing an active agent to help control the rateat which the active agent is released from the coated stent. Anembodiment of the composition, free from any active agents, can beapplied to a selected portion of the primary or reservoir coatingsubsequent to the drying of the reservoir coating. Application of thecomposition and evaporation of the solvent to form the diffusion barriercan be accomplished via embodiments of the above-described method of thepresent invention. The diffusion barrier can have a thickness of about0.2 microns to about 10 microns. It is understood by one of ordinaryskill in the art that the thickness of the diffusion barrier is based onfactors such as the type of stent, the type of procedure for which thestent is employed, and the rate of release that is desired. As describedabove with reference to the primary or reservoir coating, a final heattreatment can be conducted to remove essentially all of the solvent(s)from the optional diffusion barrier.

Either of the four layers or any combination of them can be formed usinginvention methods.

EXAMPLES

The embodiments of the present invention will be illustrated by thefollowing set forth examples, which are being given by way ofillustration only and not by way of limitation. All parameters and dataare not to be construed to unduly limit the scope of the embodiments ofthe invention.

Example 1

Four 8 mm Multi-Link TETRA stents (available from Guidant Corporation)were coated using embodiments of the method of the present invention.The stents were cleaned by sonication in water, followed by sonicationin isopropanol. The steins were dried at 70° C. and plasma cleaned in anargon plasma chamber.

Each unexpanded stent was positioned on a mandrel such that the mandrelcontacted the stent at its opposing ends. An EFD 780S spray device withVALVEMATE 7040 control system (manufactured by EFD Inc., EastProvidence, R.I.) was used to apply the coating compositions to thestents. The spray nozzle was adjusted to provide a distance from thenozzle tip to the outer surface of the stent of approximately 4.5 cm anda spray angle of approximately 90° relative to the horizontal stents.The atomization pressure was set to be maintained throughout the coatingprocess at 20 psi.

Each stent was passed under the spray nozzle for about 2 seconds. Acomposition containing 2% (w/w) poly-n-butyl methacrylate (PBMA) 337K incyclohexanone:ethyl acetate (1:1) was sprayed onto one stent. Acomposition containing 2% (w/w) PBMA 649K in cyclohexanone:ethyl acetate(1:1) was sprayed onto two stents. A composition containing 2% (w/w)PBMA 857K in cyclohexanone:ethyl acetate (1:1) was sprayed onto onestent. Each stent was rotated about the stent's central longitudinalaxis at a speed of 3 rpm during coating. After a waiting period of 1second following the application of the respective compositions, warmair of approximately 80° C. was directed from an air gun onto each stentfor 15 seconds to remove most of the solvents. The spraying-blowingcycle was repeated to deposit thirty-four layers on each stent, with await time of 5 seconds between each cycle. The coated stent was allowedto dry for about 60 minutes under vacuum conditions in an oven at atemperature of about 70° C. Each of the four coated stents had auniform, smooth coating. In addition, the stent sprayed with 2% (w/w)PBMA 857K in cyclohexanone:ethyl acetate (1:1) was submitted for asimulated use test and was found to have good mechanical properties, nocracking, and good coating adhesion.

Example 2

An 8 mm Multi-Link TETRA stent was coated using embodiments of themethod of the present invention. The stent was cleaned by placement inan ultrasonic bath of isopropyl alcohol solution for 15 minutes. Thestent was dried and plasma cleaned in a plasma chamber.

A composition containing 2% (w/w) poly-n-butyl methacrylate (PBMA) and2% (w/w) quinoline yellow dye in chloroform:cyclohexanone (9:1) wasprepared.

The unexpanded stent was positioned on a mandrel such that the mandrelcontacted the stent at its opposing ends. An EFD 780S spray device withVALVEMATE 7040 control system was used to apply the coating compositionto the stent. The spray nozzle was adjusted to provide a distance fromthe nozzle tip to the outer surface of the stent of 1.25 inches (3.18cm) and a spray angle of approximately 90° relative to the horizontalstent. The atomization pressure was set to be maintained throughout thecoating process at 15 psi.

The stent was passed under the spray nozzle for about 1 second. Thestent was rotated about the stent's central longitudinal axis at a speedof 3 rpm during coating. Warm air of approximately 100° C. was directedfrom an air gun onto the stent for 4 seconds to remove most of thesolvents. The spraying-heating cycle was repeated to deposit fortylayers on the stent, depositing about 300 micrograms of coating. Thecoated stent was allowed to dry for about 3 hours under vacuumconditions at a temperature of about 75° C. The coated stent had auniform, smooth coating with an estimated dye content of about 130micrograms or 43% of the total amount of coating deposited.

Example 3

An 8 mm Multi-Link TETRA stent was coated using embodiments of themethod of the present invention. The stent was cleaned by placement inan ultrasonic bath of isopropyl alcohol solution for 15 minutes. Thestent was dried and plasma cleaned in a plasma chamber.

A primer composition containing 2% (w/w) poly-n-butyl methacrylate(PBMA) was prepared. A reservoir composition containing 2% (w/w) PBMAand 2.7% (w/w) ethyl eosin dye in methanol:cyclohexanone (1:1) was alsoprepared. In addition, a diffusion barrier composition containing 2%(w/w) PBMA was prepared.

The unexpanded stent was positioned on a mandrel such that the mandrelcontacted the stent at its opposing ends. An EFT) 780S spray device withVALVEMATE 7040 control system was used to apply the various compositionsto the stent. The spray nozzle was adjusted to provide a distance fromthe nozzle tip to the outer surface of the stent of 1.25 inches (3.18cm) and a spray angle of approximately 90° relative to the horizontalstent. The atomization pressure was set to be maintained throughout thecoating process at 15 psi. The stent was rotated about the stent'scentral longitudinal axis at a speed of 3 rpm during coating.

The primer composition was applied to the stent by passing the stentunder the spray nozzle for about 0.75 second. Warm air of approximately100° C. was directed from an air gun onto the stent for 8 seconds toremove most of the solvents and form a primer layer on the stent. Thereservoir composition was then applied to the primered stent by passingthe stent under the spray nozzle for about 0.75 second. Warm air ofapproximately 100° C. was directed from an air gun onto the stent for 4seconds to remove most of the solvents. The spraying-heating cycle wasrepeated to deposit forty layers on the stent, depositing about 419micrograms of the reservoir coating. The coated stent was allowed to dryfor about 3 hours under vacuum conditions at a temperature of about 75°C. The barrier layer composition was then applied to thereservoir-coated stem by passing the stent under the spray nozzle forabout 0.75 second. Warm air of approximately 100° C. was directed froman air gun onto the stent for 4 seconds to remove most of the solvents.The spraying-heating cycle was repeated to deposit about 70 microgramsof the diffusion barrier. The coated stent was allowed to dry overnightunder vacuum conditions at a temperature of about 75° C. The coatedstent had a uniform, smooth coating with an estimated dye content ofabout 224 micrograms or 53% of the total amount of coating deposited.

Example 4

An 8 mm Multi-Link TETRA stent was coated using embodiments of themethod of the present invention. The stent was cleaned by placement inan ultrasonic bath of isopropyl alcohol solution for 15 minutes. Thestent was dried and plasma cleaned in a plasma chamber.

A composition containing 2% (w/w) poly-n-butyl methacrylate (PBMA) and2% (w/w) quinoline yellow dye in chloroform:cyclohexanone (9:1) wasprepared.

The unexpanded stent was positioned on a mandrel such that the mandrelcontacted the stent at its opposing ends. An EFD 780S spray device withVALVEMATE 7040 control system was used to apply the composition to thestent. The spray nozzle was adjusted to provide a distance from thenozzle tip to the outer surface of the stent of 1.25 inches (3.18 cm)and a spray angle of approximately 90° relative to the horizontal stent.The atomization pressure was set to be maintained throughout the coatingprocess at 15 psi.

The stent was passed under the spray nozzle for about 1.5 second. Thestent was rotated about the stent's central longitudinal axis at a speedof 3 rpm during coating. Warm air of approximately 100° C. was directedfrom an air gun onto the stent for 4 seconds to remove most of thesolvents. The spraying-heating cycle was repeated to deposit 3 layers onthe stent, depositing about 115 micrograms of coating. The coated stentwas allowed to dry for about 3 hours under vacuum conditions at atemperature of about 75° C. The coated stent had a uniform, smoothcoating with an estimated dye content of about 38 micrograms or 33% ofthe total amount of coating deposited.

Example 5

To determine the maximum amount of coating that could be deposited on an8 mm stent without visible webbing, a Multi-Link TETRA stent was coatedusing the same coating composition and parameters as described inExample 4. The spraying-heating cycle was repeated until 790 microgramsof coating had been deposited on the stent, at which time no webbing wasobserved.

Example 6

An 8 mm Multi-Link TETRA stent was coated using embodiments of themethod of the present invention. The stent was cleaned by placement inan ultrasonic bath of isopropyl alcohol solution for 15 minutes. Thestent was dried and plasma cleaned in a plasma chamber.

A composition containing 2% (w/w) poly-n-butyl methacrylate (PBMA) and2% (w/w) solvent blue dye in chloroform:cyclohexanone (9:1) wasprepared.

The unexpanded stent was positioned on a mandrel such that the mandrelcontacted the stent at its opposing ends. An EFD 780S spray device withVALVEMATE 7040 control system was used to apply the composition to thestent. The spray nozzle was adjusted to provide a distance from thenozzle tip to the outer surface of the stent of 1.25 inches (3.18 cm)and a spray angle of approximately 90° relative to the horizontal stent.The atomization pressure was set to be maintained throughout the coatingprocess at 15 psi.

The stent was passed under the spray nozzle for about 1.5 seconds. Thestent was rotated about the stent's central longitudinal axis at a speedof 3 rpm during coating. Warm air of approximately 100° C. was directedfrom an air gun onto the stent for 4 seconds to remove most of thesolvents. The spraying-heating cycle was repeated to deposit about 130micrograms of coating. The coated stent was allowed to dry for about 3hours under vacuum conditions at a temperature of about 75° C. Thecoated stent had a uniform, smooth coating with a estimated dye contentof about 85 micrograms or 66% of the total amount of coating deposited.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from theembodiments of this invention in its broader aspects and, therefore, theappended claims are to encompass within their scope all such changes andmodifications as fall within the true spirit and scope of theembodiments of this invention. Additionally, various embodiments havebeen described above. For convenience's sake, combinations of aspects(such as monomer type or gas flow rate) composing invention embodimentshave been listed in such a way that one of ordinary skill in the art mayread them exclusive of each other when they are not necessarily intendedto be exclusive. But a recitation of an aspect for one embodiment ismeant to disclose its use in all embodiments in which that aspect can beincorporated without undue experimentation. In like manner, a recitationof an aspect as composing part of an embodiment is a tacit recognitionthat a supplementary embodiment exists that specifically excludes thataspect.

Moreover, some embodiments recite ranges. When this is done, it is meantto disclose the ranges as a range, and to disclose each and every pointwithin the range, including end points. For those embodiments thatdisclose a specific value or condition for an aspect, supplementaryembodiments exist that are otherwise identical, but that specificallyexclude the value or the conditions for the aspect.

What is claimed is:
 1. A stent comprising a coating, the coatingconsisting of a poly(D,L-lactic acid) (PDLLA) and a macrocyclic drug,wherein the PDLLA has a degree of crystallinity of less than 20 percent,the measurement being by weight of the amount of polymer that is in theform of crystallites as measured by differential scanning calorimetry,wherein the coating has a thickness of 0.05 microns to 10 microns, andwherein the stent on which the coating is disposed is made from abioabsorbable polymer.
 2. The stent of claim 1, wherein the drug israpamycin.